The retrovirus, HIV which is a virus within the family of Retroviridae, is the etiological agent of AIDS and AIDS-related complexes. Viral replication occurs only within host cells and is dependent upon host cellular functions. The production of functional viral proteins is critical to this replication. Protein synthesis is accomplished by translation of the open reading frames into polyprotein constructs, corresponding to the gag, pol, and env reading frames, which are processed, at least in part, by a viral protease into the functional proteins. The proteolytic activity provided by the viral protease in processing the polyproteins cannot be provided by the host and is essential to the life cycle of the retrovirus. Methods to express retroviral proteases in E. coli have been disclosed by Debouck, et al., Proc. Natl. Acad. Sci. USA, 8903-06 9 (1987) and Graves, et al., Proc. Natl. Acad. Sci. USA, 85, 2449-53 (1988) for the HIV-1 virus. In fact, it has been demonstrated that retroviruses which lack the protease, or contain a mutated form of it, lack infectivity. See Katoh et al., Virology, 145, 280-92 (1985), Crawford et al., J. Virol, 53, 899-907 (1985) and Debouck et al., Proc. Natl. Acad. Sci. USA, 84, 8903-6 (1987). Inhibition of retroviral proteases, such as HIV protease, presents a method of therapy for retroviral diseases, such as AIDS. There exists a need for compounds which inhibit retroviral protease activity for pharmaceutical use to provide therapy for diseases which are caused by such retroviruses.
EP-A 352,000 and EP-A 337,714, which are incorporated herein by reference, disclose peptide-like compounds which inhibit retroviral proteases. Neither of these references disclose compounds having the constrained peptide backbone conformation which is the significant feature of the inhibitor compounds of the present invention.
Gamma turn mimics have been reported in the following-publications: Huffman et al., Peptides, Chemistry and Biology, Proceedings of the Tenth American Peptide Symposium, (Marshall, G., ed.), ESCOM, Luden, 1988, pp. 105-8. Huffman et al., Synthetic Peptides: Approaches to Biological Problems. UCLA Symposium on Molecular and Cellular Biology, Vol. 86 (Tam, J. and Kaiser, E., eds.) Alan R. Liss, Inc., New York, 1988. Huffman et al., 10th American Peptide Symposium, Abstract, May 1987. Callahan et al., 30th Organic Symposium, Abstract, June 1987. Lack of significant biological activity was reported.
X-ray crystal structures of certain aspartic acid-based enzyme inhibitors bound to the active sites of the enzymes reveal that a C-7 or gamma turn conformation about the amino acid in the P1 site is compatible with the pharmacophore for inhibition. We have found that compounds containing synthetic mimics, which constrain the peptide backbone conformation, are inhibitors of HIV protease. They are also inhibitors of renin.